Toothpastes

ABSTRACT

The invention relates to a toothpaste containing a therapeutic agent through the use of which there is produced a sustained and enhanced level of the therapeutic agent in the oral fluids. The toothpaste comprises 30 to 75% by weight of an abrasive cleaning agent consisting at least in part of calcium carbonate, a therapeutic agent, 0.01 to 0.6% by weight of a flavouring agent, and 0.002 to 0.1% by weight of sodium saccharinate or the equivalent amount of another sweetening agent.

This invention relates to toothpastes, more particularly toothpasteswhich comprise an inorganic fluorine-containing therapeutic agent forcombating dental caries. Toothpastes include both opaque products andtransparent gel products but do not include prophylactic pastes.

It is well known to include water-soluble ionic fluorine-containingsalts, for example sodium fluoride or sodium monofluorophosphate, intoothpastes and that by the regular daily use of such toothpastes theincidence of dental caries can be reduced. It is believed that thefluoride ion, or monofluorophosphate ion, interacts with the toothsubstance and increases its resistance to acid attack and also aidsremineralisation of incipient caries lesions. However, the opportunityfor this efficacious interaction to occur is short-lived because theoral fluoride level falls off rapidly after use of a mouthwash ortoothpaste.

Evidence is given by Fejerskov et al (Acta Odontol. Scand., 1981, 39,241-249) that fluoride, even in low concentrations, is necessary in theoral fluids to obtain maximum caries inhibition concluding thatcontinuous or frequent supplementation of fluoride to oral fluids ismandatory particularly in cases of increased cariogenic challenge at anyage.

Attempts have been made to provide means for maintaining a certainconcentration of fluoride ions in the mouth over a longer period. Thesehave included proposals for locating a fluoride ion source in the mouth,for example as part of an orthodontic appliance. More recently, Williamset al, Journal of Pedodontics, Spring 1982, 218-228, have disclosedadhering fluoride-containing microcapsules to teeth with guar gum toprovide a sustained release source of fluoride. Spooner et al, Int. JPharmaceutics, 15, 177-184, 1983 describe a device located at ademineralised enamel surface for the sustained release of fluoride ionswhich device comprises a supply of particles of calcium fluoridecontained within a membrane Ogaard et al, Caries Res., 17, 520-524, 1983postulate that calcium fluoride formed in outer layers of tooth enamelby treatment with an aqueous solution of sodium fluoride might wellserve as a significant reservoir of fluoride and may be of primeimportance concerning the cariostatic effect of the retained fluoride.

In our EP-A-228 209 and EP-A-263 638 we have described other means formaintaining a certain concentration of fluoride ions in the mouth. InEP-A-228 209 a means is described for the attachment to oral surfaces ofparticles which slowly release a therapeutic agent, especially fluorideions. In EP-A-263 638 the desired effect is obtained through thedeposition in the mouth of particles of freshly precipitated calciumfluoride.

The present invention is based on our surprising discovery that asustained level of fluoride in the oral fluids can be obtained by theuse of a fluoride toothpaste which during brushing of the teeth with thetoothpaste stimulates the flow of saliva substantially less thanconventional products. Reduced salivary flow has the effect of lesseningthe dilution of the fluorine-containing agent in the oral fluids andthis promotes a sustained therapeutic effect.

Conventional commercial toothpastes contain ingredients which markedlystimulate salivary flow. In particular we have found that commonlyemployed ingredients which have a marked stimulatory effect on salivaryflow are flavouring oils and sweetening agents. In toothpastes inaccordance with this invention the amounts of these ingredients arereduced relative to the amounts used in conventional products.

According to the present invention there is provided a toothpastecontaining a calcium-free abrasive cleaning agent, an inorganic ionicfluoride, 0.01 to 0.6% by weight of a flavouring agent and 0.002 to 0.1%by weight of sodium saccharinate or the equivalent weight of anothersweetening agent.

The toothpaste of the present invention contains a calcium-free abrasiveagent. Examples of suitable abrasives are silica and alumina abrasives,as well as water-insoluble sodium metaphosphate and plastics materials.Abrasive agents are usually present in toothpastes in an amount of 5 to75% by weight.

The inorganic ionic fluoride anti-caries agent included in thetoothpaste of the invention is preferably sodium fluoride or sodiummonofluorophosphate or a mixture thereof. However, other inorganicfluoride salts are also known to those skilled in the art for providingfluorine in ionic form. Among such other metal salts perhaps the bestknown is stannous fluoride. The amount of the inorganic fluorideincluded in the toothpaste will generally be from about 0.05 to about 3%by weight, more particularly an amount sufficient to provide about 50 to3500 ppm of ionic fluoride (e.g. F⁻ or FPO₃ ⁻⁻).

Flavouring oils commonly used in toothpastes are peppermint oil,spearmint oil, oil of wintergreen and mixtures thereof. A number ofother flavouring oils have been suggested for use in toothpastesincluding sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemonand orange.

In the toothpaste of this invention the amount of the flavouring agentused is 0.01 to 0.6% by weight of the toothpaste. Preferred amounts are0.01 to 0.5% by weight with the most preferred range being 0.01 to 0.4%by weight.

Sodium saccharinate is a commonly used sweetening agent and othersweetening agents that may be used in toothpastes include aspartame,lactose, maltose, sodium cyclamate and thaumatin.

In the toothpastes of the invention the amount of sodium saccharinateused is 0.002 to 0.1%, preferably 0.002 to 0.06%, by weight, or there isemployed an amount of another agent imparting equivalent sweetness.

It will be appreciated by those skilled in the art that the amounts offlavouring agent and sweetening agent used in toothpastes of thisinvention are substantially less than those amounts used in conventionalcommercial products.

It has also been discovered that a further improvement is obtained bylimiting the amount of anionic surfactant that may be present in thetoothpaste. Toothpastes almost invariably comprise an anionicsurfactant. We have found that the presence of an anionic surfactant ina toothpaste comprising a fluorine-containing therapeutic agent reducesthe retention of the fluorine-containing agent in the mouth, and therebyreduces its efficacy, and it is expected that it also has an effect inthe case of other therapeutic agents. The exact mechanism by which areduction in the level of the surfactant operates to give an enhancedsustained therapeutic effect is uncertain. One possible way is bymodifying the impact of the flavouring oil in the mouth so as to lessenthe stimulation of salivary flow.

The anionic surfactant most commonly used in commercial toothpastes issodium lauryl sulphate, but other anionic surfactants have also beenused and these include sodium dodecylbenzene sulphonate, sodium lauroylsarcosinate and sodium coconut monoglyceride sulphonate.

Accordingly, preferred toothpastes of this invention comprise 0 to 1.5%by weight of anionic surfactant. In more preferred products the amountof anionic surfactant is 0 to 1% by weight with most preferred amountsbeing 0 to 0.75% by weight.

Toothpastes of this invention may include other surfactants especiallynon-ionic surfactants.

Toothpastes of the invention will also comprise the usual additionalingredients in particular humectant and a binder or thickening agent.

Humectants which may be used include glycerol, sorbitol syrup,polyethylene glycol, lactitol, xylitol or hydrogenated corn syrup. Thetotal amount of humectant present will generally range from 10% to 85%by weight of the toothpaste.

Numerous binding or thickening agents have been indicated for use intoothpastes preferred ones being sodium carboxymethylcellulose andxanthan gum. Others include natural gum binders such as gum tragacanth,gum karaya and gum arabic, Irish moss, alginates and carrageenans.Silica thickening agents include the silica aerogels and variousprecipitated silicas. Mixtures of binders and thickening agents may beused The amount of binder and thickening agent included in a toothpasteis generally between 0.1 and 15% by weight.

The following Examples illustrate the invention. All percentages hereinare by weight.

    ______________________________________                                                        %                                                                             Example No.                                                   Ingredient        1      2       3     4                                      ______________________________________                                        Alumina trihydrate                                                                              50.00  50.00   50.00 50.00                                  Sorbitol syrup (70% solution)                                                                   29.50  29.82   29.685                                                                              29.415                                 Sodium lauryl sulphate                                                                          0.15   0.075   0.15  0.30                                   Sodium carboxymethylcellulose                                                                   0.85   1.00    1.00  1.00                                   Sodium monofluorophosphate                                                                      0.76   0.455   0.455 0.455                                  Sodium saccharinate                                                                             0.02   0.01    0.02  0.04                                   Monosodium phosphate                                                                            0.31   0.31    0.31  0.31                                   (anhydrous)                                                                   Titanium dioxide  0.50   0.50    0.50  0.50                                   Flavor (spearmint oil)                                                                          0.10   0.05    0.10  0.20                                   Water             17.81  17.78   17.78 17.78                                  ______________________________________                                    

The toothpastes of this invention are characterised by relatively lowlevels of both flavouring agent and sweetening agent. Thereby when theteeth are brushed with such toothpastes there is less stimulation ofsaliva flow. This effect has been demonstrated by the applicants intests using the toothpastes of Examples 1 to 4.

For each of the toothpastes there was determined their respectiveRelative Saliva Flow Index. This index expresses the stimulated salivaflow relative to the stimulated saliva flow during use of a standardconventional product.

The test method for the determination of the Relative Saliva Flow Index(RSFI) of the toothpastes of the above Examples will now be described.

Test Method

In this saliva flow test the panellists participate in the afternoons,i.e. after their midday meal, and they are requested not to eat or drinkfor at least 30 minutes before bath step 1 and step 2 of the test.Excluded were panellists with an abnormally high or an abnormally lowunstimulated saliva flow rate.

Step 1

A panel of 10 subjects rinse for 5 seconds with 10 ml water andexpectorate, i.e. spit it out. Then after 5 mins panellists swallow,brush their teeth for 1 min using 1.5g of standard toothpaste andcollect all expectorate into a preweighed container. The container isreweighed and the weight of expectorate (W1) is obtained by difference.

Step 2

At the same time of day on the next day step 1 is repeated but with thestandard toothpaste replaced by the test toothpaste. The weight ofexpectorate from repeat step 1 is W2.

The RSFI as used herein is given by the expression ##EQU1##

The standard toothpaste has the following composition.

    ______________________________________                                        Ingredient            %                                                       ______________________________________                                        Alumina trihydrate    50.00                                                   Sorbitol syrup (70% solution)                                                                       27.00                                                   Sodium lauryl sulphate                                                                              1.50                                                    Sodium carboxymethylcellulose                                                                       0.85                                                    Sodium monofluorophosphate                                                                          0.76                                                    Sodium saccharinate   0.20                                                    Monosodium phosphate (anhydrous)                                                                    0.31                                                    Titanium dioxide      0.50                                                    Flavour (spearmint oil)                                                                             1.00                                                    Water (demineralised) to 100.00                                               ______________________________________                                    

The toothpastes of Examples 1 to 4 and the standard toothpaste were madein a conventional way.

In one test involving Example 1 the value of (W1- 1.5) for the standardtoothpaste was 3.83 (1.13), the number between brackets being thestandard deviation. In a second test involving Examples 2, 3, and 4, thevalue of (W1- 1.5) for the standard toothpaste was 4.37 (1.72).

The values of (W2 - 1.5) and the RSFI for the toothpastes of theExamples were as follows.

    ______________________________________                                        Example        W2 - 1.5  RSFI                                                 ______________________________________                                        1              2.88 (1.45)                                                                             75 (16)                                              2              3.18 (1.45)                                                                             79 (33)                                              3              3.21 (1.88)                                                                             73 (29)                                              4              3.31 (1.71)                                                                             78 (29)                                              ______________________________________                                    

Experiments were also conducted which showed the enhanced salivaryfluoride levels after use of toothpastes of the invention. The testmethod used was as follows.

1. A panel of ten adults used a non-fluoride toothpaste at home forseveral days prior to the test and during the experimental period.

2. At the time of the test, panellists brushed their teeth with 1.5 gtoothpaste for 1 minute, expectorated and then rinsed with 10 ml waterfor 5 seconds (twice).

3. Samples of saliva were collected immediately before toothpasteapplication and at regular intervals afterwards.

4. Salivary fluoride ion activities were measured using a fluoride ionspecific electrode (Orion 9409) in the presence of a buffer known in theart as TISAB (total ionic strength adjustment buffer).

5. To ensure complete conversion of monofluorophosphate ions to fluorideions before analysis, saliva samples collected within 15 minutes oftoothpaste use were incubated at 37° C. overnight whilst all samplescollected later were stored at room temperature for two days.

6. Individual pastes were tested at intervals of at least two full daysand panellists were not allowed to eat or drink during experimentalperiods.

The logarithms of the salivary fluoride ion activities were plottedagainst time and the extrapolated zero time intercept determined fromdata values obtained at times equal to and greater than 60 minutes. Thefluoride concentration corresponding to this intercept is referred tobelow as the fluoride reservoir depth (FRD) and is expressed in ppm F.The results of three different tests are indicated below.

    ______________________________________                                                             % increase in                                                                 FRD compared to:                                                                    Stan-   Modified                                   Toothpaste   FRD           dard    Standard                                   ______________________________________                                        Test 1                                                                        Standard      0.069 (0.033)**                                                                            --                                                 Formulation 1                                                                              0.166 (0.105)  141                                               Test 2                                                                        Standard     0.056 (0.037) --      51                                         Modified Standard*                                                                         0.037 (0.016) -34     --                                         Formulation 3                                                                              0.063 (0.039)  13     70                                         Test 3                                                                        Standard     0.066 (0.024) --      78                                         Modified Standard*                                                                         0.037 (0.021) -44     --                                         Formulation 2                                                                              0.089 (0.069)  35     141                                        Formulation 3                                                                              0.056 (0.028) -15     51                                         Formulation 4                                                                              0.054 (0.042) -18     46                                         ______________________________________                                         *As the Standard formulation but having a content of sodium                   monofluorophosphate of 0.455% corresponding to 600 ppm F, i.e. the same a     that of Formulations 2 to 4.                                                  **The number between the brackets is the standard deviation.             

Examples 5 to 8 are further examples of toothpastes of this invention.

EXAMPLE 5

    ______________________________________                                        Ingredient          %                                                         ______________________________________                                        Alumina trihydrate  50.00                                                     Sorbitol syrup (70% solution)                                                                     29.59                                                     Sodium lauryl sulphate                                                                            0.15                                                      Xanthan gum         1.10                                                      Sodium monofluorophosphate                                                                        0.76                                                      Zinc citrate trihydrate                                                                           1.00                                                      Sodium saccharinate 0.018                                                     Titanium dioxide    0.50                                                      Flavour (spearmint oil)                                                                           0.12                                                      Formalin            0.04                                                      Water (demineralised)                                                                             to 100.00                                                 ______________________________________                                    

EXAMPLE 6

    ______________________________________                                        Ingredient             %                                                      ______________________________________                                        Alumina trihydrate     50.00                                                  Sorbitol syrup (70% solution)                                                                        29.28                                                  Sodium lauryl sulphate 0.30                                                   Sodium carboxymethylcellulose                                                                        1.00                                                   Sodium monofluorophosphate                                                                           0.76                                                   Sodium saccharinate    0.02                                                   Monosodium phosphate (anhydrous)                                                                     0.31                                                   Titanium dioxide       0.50                                                   Flavour (spearmint oil)                                                                              0.05                                                   Water                  17.78                                                  ______________________________________                                    

EXAMPLE 7

    ______________________________________                                        Ingredient           %                                                        ______________________________________                                        Silica               18.0                                                     Sorbitol syrup (70% solution)                                                                      69.0                                                     Polyethylene glycol 1500                                                                           5.0                                                      Sodium lauryl sulphate                                                                             0.7                                                      Sodium carboxymethylcellulose                                                                      0.5                                                      Sodium fluoride      0.22                                                     Sodium saccharinate  0.06                                                     Titanium dioxide     1.0                                                      Flavour oil          0.4                                                      Water                to 100.0                                                 ______________________________________                                    

EXAMPLE 8

    ______________________________________                                        Ingredient           %                                                        ______________________________________                                        Silica               22.0                                                     Sorbitol syrup (70% solution)                                                                      50.0                                                     Polyethylene glycol 1500                                                                           5.0                                                      Sodium lauryl sulphate                                                                             0.7                                                      Sodium carboxymethylcellulose                                                                      0.65                                                     Sodium fluoride      0.22                                                     Sodium saccharinate  0.06                                                     Titanium dioxide     1.0                                                      Flavour oil          0.4                                                      Water                to 100.0                                                 ______________________________________                                    

I claim:
 1. A toothpaste comprising about 5 to about 75% by weight of acalcium-free abrasive cleaning agent, about 0.05 to about 3% of aninorganic ionic fluoride, 0.01 to 0.05% by weight of a flavouring agentand 0.002 to 0.01% by weight of a sweetening agent.
 2. A toothpaste asclaimed in claim 1 wherein the abrasive agent is silica or alumina.
 3. Atoothpaste as claimed in claim 1 wherein the inorganic fluoride isselected from the group consisting of sodium fluoride, sodiummonofluorophosphate and mixtures thereof.
 4. A toothpaste as claimed inclaim 1 comprising 0 to 1.5% by weight of an anionic surfactant.
 5. Atoothpaste as claimed in claim 4 comprising 0 to 1.0% by weight of ananionic surfactant.
 6. A toothpaste as claimed in claim 1 wherein thesweetening agent is sodium saccharinate.
 7. A toothpaste as claimed inclaim 1 wherein the sweetening agent is selected from the groupconsisting of sodium saccharinate, aspartame, sodium cyclamate andthaumatin.
 8. A toothpaste as claimed in claim 5 wherein the anionicsurfactant is a sodium lauryl sulphate.
 9. A method to reduce salivaryflow in an oral cavity to effect a longer retention of fluoride ions insaid oral cavity, said method comprising applying teeth a toothpastecomprising from about 5 to about 75% by weight of a calcium-freeabrasive cleaning agent, about 0.05 to about 3% of an inorganic ionicfluoride, 0.01 to 0.6% by eight of a flavouring agent and 0.002 to 0.1%by weight of a ssweetening agent, the amount of said flavouring andsweetening agent being sufficiently low to reduce their normalstimulatory effect upon said salivary flow.
 10. A method according toclaim 9 wherein the amount of flavouring agent is 0.001 to 0.5% byweight.
 11. A method according to claim 9 wherein said sweetening agentis sodium saccharinate present at a level from 0.002 to 0.06%.
 12. Amethod according to claim 9 wherein said sweetening agent is selectedfrom the group consisting of sodium saccharinate, aspartame, sodiumcyclamate and thaumatin.